Pharmaceutical compositions and methods utilizing a d-amino acid

ABSTRACT

The present invention provides a pharmaceutical composition for oral administration comprising a D-amino acid combined with an antioxidant selected from the group consisting of vitamin E, vitamin C, a glutathione or a precursor thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This is Continuation of co-pending U.S. patent application Ser. No.15/436,901 filed Feb. 20, 2017, which was a Continuation of U.S. patentapplication Ser. No. 12/350,901, filed Jan. 8, 2009, now abandoned,which claimed the benefit of Israel Patent Application No. IL188681,filed Jan. 8, 2008. The contents of the foregoing applications areincorporated by reference herein in their entirety.

FIELD

The present invention relates to a pharmaceutical composition fortreating a neuropsychiatric disorder and to methods utilizing the same.

BACKGROUND

D-serine is a naturally occurring amino acid and one of a class of aminoacids that is known to be useful for treatment of neuropsychiatricdisorder but which may cause nephrotoxicity when administered torodents. In the brain, D-serine serves as a modulator ofN-methyl-D-aspartate (NMDA)-type glutamate receptors. Deficiencies ofD-serine or of NMDA neurotransmission may contribute to thepathophysiology of multiple neuropsychiatric disorders includingschizophrenia, Alzheimers disease, attention deficit hyperactivitydisorder, autism, depression, and movement disorders (Javitt 2000; Tsai2001). It has been proposed therefore that oral administration ofD-serine at doses of 1 mg-100 g may serve as a novel treatment for thesedisorders. Clinical use of D-serine and of similar D-amino acids ispotentially limited by concerns regarding renal toxicity, which has beenobserved in rodent species, especially in the rat. Thus, compounds areneeded that prevent nephrotoxicity when given orally along withD-serine.

The ability of D-serine to induce renal injury in rats is reviewed by(Kaltenbach et al 1979). D-serine induced nephrotoxicity has beendemonstrated since at least 1942, when it was noted an injurious actionof DL-serine administered by stomach tube in rats maintained on asynthetic deficient in protrain and in B vitamins. Subsequent studiesdemonstrated that administration of 100 mg DL-serine induced acute renalnecrosis at the junction of the renal cortex and medulla which wasobserved when serine was added to either stock diet or diet deficient inB vitamins. Lesions were consistently produced reliable with doses assmall as 5 mg D-serine per 100 g. Despite intensive investigation, themechanism by which orally administered D-serine induces nephrotoxicityremains an area of active research.

Nephrotoxicity induced by D-serine and other related amino acids ischaracterized by corticomedullary pathology, such as necrosis of thestraight segment of the proximal tubule in the rat kidney following oralor intravenous administration. Severity of nephrotoxicity can bemonitored by assessment of serum levels of creatanine and BUN(Orozco-Ibarra et al 2007). Similar nephrotoxicity can be induced bycompounds structurally related to D-serine, includingD-2,3-aminopropionic acid (DAPA) (Kaltenbach et al 1979).

Wachstein et al. investigated the ability of various compounds toreverse the effects of orally administered DL-serine (100 mg) asdiscussed by Kaltenbach et al., (Kaltenbach et al 1982). In all cases,test compounds were administered either subcutaneously orintramuscularly. These studies showed that nephrotoxic effects ofDL-serine could be blocked by either DL-methionine or glutathione (GSH)when co-injected with D-serine in rats protects against thenephrotoxicity. Other compounds showing partial or full prevention oftoxicity included glycine, DL-threonine, glycolic acid and sodiumlactate. Several other compounds, however, were relativley ineffectiveincluding L-cysteine, sodium thioglycollate, 2,3 dithiopropanol (BAL),DL-alpha-alanine, L-histidine, L-arginine, DL-valine, butyric acid,D-glucose, sodium chloride, and sodium acetate. It was hypothesized thatbeneficial effects of these compounds were due to suppression of tubularreabsorption of the D-isomer.

Subsequent studies demonstrated significant protective effects ofD-alanine, D-threonine, D-homoserine, DL-alpha-methylserine,beta-hydroxy-DL-leucine, and alpha-aminoisobutryic acid. As inWachstein, all compounds were administered by injection prior toD-serine administration (Kaltenbach et al 1982). More recently,protective effects of alpha-aminoisobutyric acid (AIB) have beenconfirmed. It is hypothesized that this compound prevents uptake ofD-serine into renal tubular cells, thereby limiting its nephrotoxiceffects (Krug et al 2007).

In general, nephrotoxic effects of D-serine are considered to resultfrom its metabolism by D-aminoacid oxidase (DAAO), which liberatesreactive oxygen species such as peroxide (Krug et al 2007; Maekawa et al2005; Williams and Lock 2005). This theory is supported by theobservation that D-serine is not nephrotoxic is rats lacking-DAAO(Maekawa et al 2005), and that toxicity can be prevented by intrarenalinjection of equimolar glutathione with D-serine (Krug et al 2007) or byintraperitoneal administration of large doses of sodium benzoate(Williams and Lock 2005). However, this theory is challenged by a recentstudy that failed to detect increased reactive oxygen species orperoxidation markers in rat kidney following D-serine injection.Further, several compounds with an antioxidant effect failed to preventD-serine nephrotoxicity. (Orozco-Ibarra et al 2007). Therefore, not onlycan it be concluded from this reference that oxidative stress alone maybe an insufficient model for nephrotoxicity, but this reference alsoconstitutes a clear teaching away from the discovery of the presentinvention that in fact certain antioxidants when administered togetherwith a D-amino acid are effective for reducing the risk ofnephrotoxicity.

SUMMARY

Thus, the present invention derives from the discovery that orallyadministered precursors of glutathione (GSH), including the compoundsN-acetylcysteine and L-cysteine, prevent nephrotoxicity induced by theamino acid D-serine. The present invention provides a method for oraladministration of D-serine or similar amino acids that minimizes risksof nephrotoxicity. This formulation therefore represents a significant,clinically useful improvement over use of D-serine or other amino acidsalone as medicaments for neuropsychiatric or other medical conditions.

D-amino acids in general, and D-serine in specific are consideredappropriate therapeutics in various neuropsychiatric conditionsincluding schizophrenia, movement disorders, cognitive dysfunction,memory disorders and attentional disorders. Use of these compounds inclinical settings, however, is potentially limited by nephrotoxicity. Inanimal studies, intravenous or intraperitoneal administration ofglutathione has been shown to limit toxicity induced by D-serine.However, non-oral routes of administration are not feasible for clinicaltreatment, necessitating alternative approaches. Oral NAC administrationis a widely used treatment for hepatotoxicity, particularly followingacetominophen administration (Amirzadeh and McCotter 2002; Betten et al2007), and is equally effective to iv NAC in the majority of cases(Kanter 2006). However, oral NAC or other glutathione precursors havenot been found to be effective treatments for nephrotoxicity induced bya wide variety of agents including contrast agents and chemotherapies.Despite intensive investigation of treatments that might reverseD-serine nephrotoxicity, oral NAC or other glutathione precursors havenot been evaluated previously against D-serine-induced nephrotoxicityeither in humans or animal models.

According to the present invention, there is now some evidencesuggesting that the combination of NAC and L-cysteine (Groups B&C) aresuperior to either agent alone (Groups D&E) as seen in the examples hereand after. No one has previously suggested using the presently suggestedcombined treatment, and the observed synergy is an unexpected finding.

Furthermore, as far as applicant was able to determine, the researchleading to the common invention was the first study to evaluate NAC incombination with L-cysteine. The observed efficacy of both NAC andL-cysteine in the present examples is however consistent with theconcept that NAC functions largely by supplying L-cysteine to the portalcirculation as postulated by Dilger and Baker 2007.

More specifically, according to the present invention, there is nowprovided a pharmaceutical composition for oral administration comprisinga D-amino acid combined with an antioxidant selected from the groupconsisting of vitamin E, vitamin C, a glutathione or a precursorthereof.

In preferred embodiments of the present invention the D-amino acid isselected from the group consisting of D-serine, D-alanine, D-cysteine,D-homocysteine, or D-threonine

In some preferred embodiments of the present invention the antioxidantis glutathione or a precursor thereof.

In other preferred embodiments of the present invention the glutathioneprecursor is selected from the group consisting of L-cysteine orN-acetyl-L-cysteine and racemic versions or combinations thereof. Inother preferred embodiments of the present invention the antioxidant isvitamin E while in yet other preferred embodiments the antioxidant isvitamin C.

Preferably, the D-amino acid and antioxidant are present in molar ratiosof between 1:10 and 10:1.

In another aspect of the present invention, there is provided a methodfor treating a neuropsychiatric disorder characterized by attenuatedNMDA neurotransmission comprising administering the pharmaceuticalcomposition defined above.

In some preferred embodiments of the present invention theneuropsychiatric disorder is schizophrenia, schizophreniform disorder,psychosis NOS, or prodromal schizophrenia.

In other preferred embodiments of the present invention theneuropsychiatric disorder is Alzheimer's disease.

The present invention also provides a method for treating aneuropsychiatric disorder characterized by attenuated NMDAneurotransmission in a patient, the method comprising administering to apatient diagnosed as suffering from the neuropsychiatric disorder anoral pharmaceutical composition comprising a therapeutically effectiveamount of a D-amino acid combined with a an anti-oxidant selected fromthe group consisting of vitamin E, vitamin C, a glutathione or aprecursor thereof.

Orally active compounds have been described that serve as glutathioneprecursors and protect the liver. In particular, N-acetylcysteine (NAC)is a glutathione prodrug that is currently approved for treatment ofacetaminophen-induced hepatotoxicity (Atkuri et al 2007) and also totreat glutathione deficiency. NAC has also been evaluated as potentialtreatment for nephrotoxicity induced by a variety of agents, especiallyintravenous contrast fluid (Stacul et al 2006). At present however, nooral treatments are known that prevent oxidative damage to the kidney inresponse to D-serine or other potentially nephrotoxic agents.

Although the efficacy of intravenously administered NAC againstnephrotoxicity has been shown repeatedly (Briguori et al 2007;Recio-Mayoral et al 2007), similar studies using oral NAC have not foundbenefit over hydration alone for blockade of nephrotoxicity due tointravenous contrast (Azmus et al 2005; Goldenberg et al 2004; Lawlor etal 2007; Sandhu et al 2006; Shalansky et al 2005). Previous studies havealso not found beneficial effects of oral NAC against experimentalnephrotoxicity induced by cisplatin in rats, although invtravenous NACwas effective (Dickey et al 2007). Further, it has previously beenreported that kidney NAC levels are not increased following either acuteor chronic oral administration in rat, and that NAC alone may worsenoxidative stress (Arfsten et al 2007). Other cysteine prodrugs have alsobeen shown to be ineffective (Li et al 2002). Of note, however, nostudies to date have investigated effects of orally administeredglutathione precursors on D-serine-induced nephrotoxocity in vivo, oreffects of N-acetylcysteine and other glutathione precursorsadministered in combination.

The present invention is further distinguished from prior treatments forD-amino acid-induced nephrotoxicity in that it employs oral, rather thanintravenous administration of N-acetylcysteine and L-cysteine forreversal of D-serine induced nephrotoxicity, and utilizes combinationsof glutathione precursors rather than administration of individualprecursors alone. Despite over 60 years of research in this field, noprior studies have evaluated use of oral glutathione precursors or otheranti-oxidants such as vitamin E or vitamin C against D-amino acidinduced toxicity.

The invention is useful in that it permits administration of oralD-amino acids to humans with reduced risk of nephrotoxicity. D-aminoacids, particularly D-serine, have proven effective for treatment ofneuropsychiatric disorders. The present invention therefore provides animproved method for treatment of neuropsychiatric disorders. Otherfeatures and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

Definitions

The term amino acid as used herein refers to amino acid is a moleculethat contains both amine and carboxyl functional groups. Inbiochemistry, this term refers to alpha-amino acids with the generalformula H₂NCHRCOOH, where R is an organic substituent. In the alphaamino acids, the amino and carboxylate groups are attached to the samecarbon, which is called the .alpha.-carbon. The various alpha aminoacids differ in which side chain (R group) is attached to their alphacarbon. They can vary in size from just a hydrogen atom in glycine,through a methyl group in alanine, to a large heterocyclic group intryptophan.

The term anti-oxidant as used herein refers to a molecule capable ofslowing or preventing the oxidation of other molecules. Oxidation is achemical reaction that transfers electrons from a substance to anoxidizing agent. Oxidation reactions can produce free radicals, whichstart chain reactions that damage cells. Antioxidants terminate thesechain reactions by removing free radical intermediates, and inhibitother oxidation reactions by being oxidized themselves. Examples ofantioxidants include glutathione, vitamin C, and vitamin E. The termVitamin C refers to L-ascorbate and related molecules. The term VitaminE refers is the general name for two classes of molecules (tocopherolsand tocotrienols) having vitamin E activity in nutrition

The term “neuropsychiatric disorder” as used herein refers to a diseasehaving a pathophysiological component of attenuated NMDAreceptor-mediated neurotransmission. Examples of such disorders includeschizophrenia, Alzheimer's disease, autism, depression, benignforgetfulness, childhood learning disorders, close head injury, andattention deficit disorder.

The term “schizophrenia” as used herein refers to a psychiatric disorderthat includes at least two of the following: delusions, hallucinations,disorganized speech, grossly disorganized or catatonic behavior, ornegative symptoms. The term “schizophreniform disorder” as used hereinrefers to a psychiatric disorder that are identical to those ofschizophrenia except for two differences: the total duration of theillness (including prodromal, active, and residual phases) is at least 1month but less than 6 months and impaired social or occupationalfunctioning during some part of the illness is not required (although itmay occur). The term “psychosis NOS” as used herein refers to apsychiatric disorder comprising a psychosis but not meeting criteria foreither schizophrenia or schizophreniform disorder. Patients can bediagnosed as having schizophrenia, schizophreniform disorder orpsychosis NOS using the DSM-IV criteria (APA, 1994, Diagnostic andStatistical Manual of Mental Disorders (Fourth Edition), Washington,D.C.). The term “prodromal schizophrenia” refers to a condition in whichsymptoms of schizophrenia are present in attenuated form, so that fullcriteria for a schizophrenic disorder are not present.

The term “Alzheimer's Disease” as used herein refers to a progressivemental deterioration manifested by memory loss, confusion anddisorientation beginning in late middle life and typically resulting indeath in five to ten years. Pathologically, Alzheimer's Disease can becharacterized by thickening, conglutination, and distortion of theintracellular neurofibrils, neurofibrillary tangles and senile plaquescomposed of granular or filamentous argentophilic masses with an amyloidcore. Methods for diagnosing Alzheimer's Disease are known in the art.For example, the National Institute of Neurological and CommunicativeDisorders and Stroke-Alzheimer's Disease—and the Alzheimer's Disease andRelated Disorders Association (NINCDS-ADRDA) criteria can be used todiagnose Alzheimer's Disease (McKhann et al., 1984, Neurology34:939-944). The patient's cognitive function can be assessed by theAlzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog; Rosenet al., 1984, Am. J. Psychiatry 141:1356-1364).

The term “autism” as used herein refers to a state of mentalintroversion characterized by morbid self-absorption, social failure,language delay, and stereotyped behavior. Patients can be diagnosed assuffering from autism by using the DSM-IV criteria.

The term “depression” as used herein refers to a clinical syndrome thatincludes a persistent sad mood or loss of interest in activities, whichlasts for at least two weeks in the absence of treatment. The DSM-IVcriteria can be used to diagnose patients as suffering from depression.

The term “benign forgetfulness,” as used herein, refers to a mildtendency to be unable to retrieve or recall information that was onceregistered, learned, and stored in memory (e.g., an inability toremember where one placed one's keys or parked one's car). Benignforgetfulness typically affects individuals after 40 years of age andcan be recognized by standard assessment instruments such as theWechsler Memory Scale (Russell, 1975, J. Consult Clin. Psychol.43:800-809).

The term “childhood learning disorders” as used herein refers to animpaired ability to learn, as experienced by certain children. Suchlearning disorders can be diagnosed by using the DSM-IV criteria.

The term “closed head injury,” as used herein, refers to a clinicalcondition after head injury or trauma which condition can becharacterized by cognitive and memory impairment. Such a condition canbe diagnosed as “amnestic disorder due to a general medical condition”according to DSM-IV.

The term “attention deficit disorder,” as used herein, refers to atdisorder that is most commonly exhibited by children and which can becharacterized by increased motor activity and a decreased attentionspan. The DSM-IV criteria can be used to diagnose attention deficitdisorder.

The terms “D-serine” and “D-alanine” as used herein refer to the Disomers of the amino acids serine and alanine, respectively. As Disomers, rather than L isomers, these amino acids are not naturallyfound in proteins.

The term “nephrotoxicity” or “renal toxicity” as used herein refers todrug-induced damage to the kidney and, particularly, to necrosis of therenal tubules. Such damage may be caused by any of a number ofnephrotoxic agents including aminoglycosides, cis-platinum, intravenouscontrast, and D-amino acids.

The term “pharmaceutical treatment” as used herein refers to anypharmacological agent, nutritional product, micronutrient or other suchagent whether or not currently approved that is used to alleviatesymptoms of a neuropsychiatric disorder. Such treatments may be usedeither in single dose or in repeated doses over days, weeks, months,years or lifetime of an individual.

The term “glutathione” or “GSH” as used herein refers to a tripeptidecomprised of the amino acids L-cysteine, L-glutamate and glycine. Itcontains an unusual peptide linkage between the amine group of cysteineand the carboxyl group of the glutamate side chain. It is synthesizedfirst by combination of L-glutamate and L-cysteine to form the compoundgamma-glutamylcysteine, whereafter glycine is added to the C-terminal ofgamma-glutamylcysteine to form the glutatione tripeptide. N-acetylcysteine (NAC) is an N-acetylated form of the amino acid L-cysteine thathas been approved for pharmaceutical use in the USA. The term“glutathione precursor” refers to the amino acids or intermediates thatparticipate in glutathione synthesis, or compounds that readilyinterconvert with such agents.

While the invention will now be described in connection with certainpreferred embodiments in the following examples so that aspects thereofmay be more fully understood and appreciated, it is not intended tolimit the invention to these particular embodiments. On the contrary, itis intended to cover all alternatives, modifications and equivalents asmay be included within the scope of the invention as defined by theappended claims. Thus, the following examples which include preferredembodiments will serve to illustrate the practice of this invention, itbeing understood that the particulars shown are by way of example andfor purposes of illustrative discussion of preferred embodiments of thepresent invention only and are presented in the cause of providing whatis believed to be the most useful and readily understood description offormulation procedures as well as of the principles and conceptualaspects of the invention.

EXAMPLE

The example below illustrates how orally administered glutathioneprecursors may be used to minimize nephrotoxic effects of orallyadministered D-serine. Subjects consisted of Sprague Dawley rats, whichare known to be sensitive to nephrotoxic effects of D-serine. Rats weredivided into 5 separate groups of four male and four female animalseach. The groups received the following treatments by oral gavage, inaddition to standard diet:

Group A: D-serine alone;Group B: D-serine, L-cysteine and N-acetylcysteine in a ratio of 4:3:1;Group C: D-serine, L-cysteine and N-acetylcysteine in a ratio of 2:1:1;Group D: D-serine, L-cysteine and N-acetylcysteine in a ratio of 1:0:1;andGroup E: D-serine, L-cysteine and N-acetylcysteine in a ratio of 1:1:0.

In addition, a control group received only standard diet. Compounds A,B, C, D & E were administered by single oral gavage at the doses of 50mg/kg, 100 mg/kg, 200 mg/kg & 400 mg/kg body weight and at the dosevolume of 5 ml/kg. Effects of various doses were investigated in asequential manner starting with 50 mg/kg. Dose level was doubled everythree days up to four doses (50 mg, 100 mg, 200 mg & 400 mg).

During the study, no significant mortality was observed in any group.All animals survived until study termination. Further, all animals werefree of clinical abnormalities up to the dose of 400 mg/kg.

Nephrotoxicity was assessed in two ways: first, by creatanine levels andsecond by histophathology at necropsy.

Creatanine levels during D-serine treatment are shown in Table 1. Bothcontrol and D-serine alone groups showed a significant increase increatanine levels during chronic treatment, as did Groups B and C, butnot groups D (D-serine+N-acetylcysteine) and E (D-serine+L-cysteine).For all experimental groups (Groups B-E), the degree of increase increatanine during treatment with combined treatment was significantlyless than during treatment with D-serine alone. Further, for both groupsD and E, the degree of increase in creatanine level was significantlyless than for the control group. The degree of creatanine increaseduring treatment was small in both groups D and E and did not differsignificantly between these two treatments. These findings indicate thatL-cysteine and NAC, alone or in combination, significantly reduce levelsof creatanine increase seen with D-serine treatment alone.

TABLE 1 Ratio D-ser:L- Group cyst:N- Pre-treatment Post-treatment ChangeT-test T-test Assignment acetylcyst Mean stdev mean stdev mean stdevpost vs. pre vs. D-ser alone Control Control 0.67 0.03 0.77 0.06 0.100.08 0.01 A D-serine 0.65 0.03 0.77 0.02 0.12 0.04 0.00 alone (1:0:0) B4:3:1 0.65 0.03 0.74 0.03 0.10 0.03 0.00 0.0406 C 2:1:1 0.65 0.02 0.720.04 0.07 0.04 0.01 0.0111 D 1:0:1 0.65 0.02 0.69 0.02 0.04 0.03 0.220.0000 E 1:1:0 0.64 0.04 0.68 0.05 0.04 0.06 0.92 0.0003

Potential nephrotoxic effects of D-serine alone or in combination withL-cysteine or N-acetylcysteine were also evaluated by histopathologicalexamination at necropsy. The kidney section in these studies showedfeatures of early tubular nephrosis changes, especially involving thetubular structure of medullary and corticomedullary junction whencompared with the kidney section of control animals, indicating earlynephrotoxic changes induced by the test compounds. The mean severitygrade of tubular nephrosis across compounds is show in Table 2, with theD-serine group showing a mean nephrosis grade of 1.91 (mild). Both the4:3:1 (Group B) and 2:1:1 (Group C) combinations of D-serine, L-cysteineand N-acetylcysteine showed reduced nephrosis ratings compared toD-serine alone, although nephrosis ratings with combined D-serine andL-cysteine (Group D) alone or combined D-serine and N-acetylcysteinealone (Group E) were slightly higher than those with D-serine alone(Group A).

Taken together, these findings indicate that a 2:1:1 ratio ofD-serine:L-cysteine:N-acetylcysteine produces both decreased rise increatanine and also less evidence of histopathological evidence ofnephrotoxicity vs. D-serine alone, and thus represents a preferentialoral formulation. Other combinations also show superiority in either thecreatanine or hydronephrosis assay with no significant inferiority ineither assay and thus may also be used as embodiments of this invention.

TABLE 2 Table 2: Results of histopathological examination NephrosisGroup Compostion and ratio level Control Vehicle Control (Water) AD-serine alone 1.91 B D-serine + L-cysteine + N-acetylcysteine (4:3:1)1.00 C D-serine + L-cysteine + N-acetylcysteine (2:1:1) 1.33 DD-serine + L-cysteine + N-acetylcysteine (1:0:1) 2.00 E D-serine +L-cysteine + N-acetylcysteine (1:1:0) 2.00

DETAILED DESCRIPTION

The invention describes a method for reducing risk of nephrotoxicityduring oral treatment with a D-amino acid, comprising a compositioncontaining a D-amino acid combined with an orally active antioxidant.The invention also describes an improved method for treating a patientdiagnosed as suffering from a neuropsychiatric disorder having a deficitin neurotransmission via the NMDA receptor, for whom D-serine treatmentmight be desirable. The present invention has the advantage ofdecreasing risk of nephrotoxicity during treatment with D-serine orother neuropsychiatric illness.

The treatment method of the invention entails administering to a patientdiagnosed as having a neuropsychiatric disorder an oral pharmaceuticalcomposition containing a therapeutically effective amount of (i) aD-amino acid including but not limited to D-serine, and (ii) an orallyeffective anti-oxidant, including but not limited to glutathione,N-acetylcysteine, L-cysteine or glutathione precursors. D-amino acids,glutathione and glutathione precursors are commercially available (e.g.Sigma Chemicals, St. Louis, Mo.)

Typically, in this invention, the antioxidant is given in molar ratiosof 10:1 to 1:10 with the D-amino acid, with preferred embodiments havingratios of between 4:1 and 1:1. Typically, the D-amino acid is given indoses of 1 g/d-100 g/d. A typical implementation of this invention,therefore, would be to administer a formulation consisting of 8 gD-serine and 2 g N-aceyticysteine, L-cysteine or a combination thereofin 1-3 daily divided doses. In all of the methods of the invention,glutathione or glutathione precursors can be combined with or replacedwith the antioxidants vitamin E or vitamin C.

In all of the methods of the invention, appropriate dosages of D-aminoacids combined with NAC, L-cysteine or other NAC precursors can readilybe determined by those of ordinary skill in the art of medicine bymonitoring the patient for signs of disease amelioration or inhibition,and increasing or decreasing the dosage and/or frequency of treatment asdesired.

The pharmaceutical compositions can be administered to the patient byany, or a combination, of several routes other than intravenous orintramuscular, such as oral, trans-mucosal (e.g., nasal, vaginal, etc.),pulmonary, transdermal, ocular, buccal, or sublingual. Solidcompositions for oral administration can contain suitable carriers orexcipients, such as corn starch, gelatin, lactose, acacia, sucrose,microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate,calcium carbonate, sodium chloride, lipids, alginic acid, or ingredientsfor controlled slow release. Disintegrators that can be used include,without limitation, micro-crystalline cellulose, corn starch, sodiumstarch glycolate and alginic acid. Tablet binders that may be usedinclude, without limitation, acacia, methylcellulose, sodiumcarboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropylmethylcellulose, sucrose, starch, and ethylcellulose.

Liquid compositions for oral administration prepared in water or otheraqueous vehicles can include solutions, emulsions, syrups, and elixirscontaining, together with the active compound(s), wetting agents,sweeteners, coloring agents, and flavoring agents. Various liquid andpowder compositions can be prepared by conventional methods forinhalation into the lungs of the patient to be treated.

Alternatively, the pharmaceutical composition can be formulated as achewing gum, lollipop, or the like.

It will be evident to those skilled in the art that the invention is notlimited to the details of the foregoing illustrative examples and thatthe present invention may be embodied in other specific forms withoutdeparting from the essential attributes thereof, and it is thereforedesired that the present embodiments and examples be considered in allrespects as illustrative and not restrictive, reference being made tothe appended claims, rather than to the foregoing description, and allchanges which come within the meaning and range of equivalency of theclaims are therefore intended to be embraced therein.

LITERATURE CITED

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I claim:
 1. A pharmaceutical composition, comprising: D-serine; and anephrotoxicity-reducing amount of L-cysteine, wherein the ratio betweenthe D-serine and the L-cysteine is between 2:1 and 1:1, and wherein thepharmaceutical composition is formulated for oral administration.
 2. Thepharmaceutical composition of claim 1, further comprising anephrotoxicity reducing amount of N-acetyl-L-cysteine.
 3. Thepharmaceutical composition of claim 1, further comprising at least oneof vitamin E and vitamin C.
 4. The pharmaceutical composition of claim2, further comprising at least one of vitamin E and vitamin C.
 5. Amethod for treating a neuropsychiatric disorder characterized byattenuated NMDA neurotransmission in a patient, the method comprising:orally administering to the patient: a therapeutically effective amountof D-serine; and a nephrotoxicity-reducing effective amount ofL-cysteine.
 6. The method of claim 5, further comprising orallyadministering to the patient a nephrotoxicity-reducing effective amountof N-acetyl-L-cysteine.
 7. The method of claim 5, further comprisingadministering to the patent at least one of an effective amount ofvitamin E and vitamin C.
 8. The method of claim 6, further comprisingadministering to the patent at least one of an effective amount ofvitamin E and vitamin C.
 9. The method of claim 5, wherein the ratiobetween the D-serine and the L-cysteine administered to the patient isbetween 2:1 and 1:1.
 10. The method of claim 5, wherein the D-serine andthe L-cysteine are provided in a combined composition.
 11. The method ofclaim 6, wherein the D-serine, the L-cysteine, and theN-acetyl-L-cysteine are provided in a combined composition.
 12. Themethod of claim 5, wherein the neuropsychiatric disease isschizophrenia.